Age-associated changes in immune function in humans and animals are quite important with regard not only to the general health of aged persons but also to the general features of the immune system itself. Elderly subjects have been shown to be more susceptible to viral and bacterial infections and are believed to be more susceptible to cancer. There have been a number of hypotheses for the diminished immune responses observed in elderly subjects including involution of the thymus, active immunosuppression, replication senescence of immune cells, cellular signaling defects, and alterations in cytokine expression profiles. However, despite the many findings on alterations in immune function with age, very little is known about the why such changes occur and how alterations in immune cell subsets and their activities influence immune function in the elderly and/or during various disease states. The ongoing work utilizes either peripheral white blood cells obtained from normal healthy volunteers of different ages or cells from aged rodents and primates to gain insight into the biological, biochemical, and molecular mechanisms underlying age-associated changes in human immune function. In comparison with immune cells obtained from younger individuals, aged leukocytes also display distinctive patterns of protein phosphorylation, cytokine synthesis and gene expression, effects on cell migration and trafficking, and cell-cycle progression. Recently, we have collaboratively examined cytokine generation by T cells and monocytes derived from 50 subjects aged 65 yr or older and concurrently studied young subjects individually matched to each old subject for sex, race, and national origin. Significant differences in the cytokine and chemokine expression by T cells and monocytes were observed between old and young subjects upon activation with many of the observed differences in cytokine generation being gender specific. These results suggest that not only can age have an impact on immune-derived cytokine generation but gender can also have an impact on the immune cell activity. Additional studies have focused on isolating and characterizing the human CD48 T cell subset, a relatively minor subset that increase in numbers and activities in autoimmune diseases but decrease with aging. This subset was found to express a unique profile of cytokines, including Serpin E1, migration inhibitory factor (MIF) and transforming growth factor-beta (TGF-beta). Upon co-culture of these cells with CD4+ or CD8+ T cells, the CD48 T cells significantly enhanced the generation of interferon-gamma and interleukin-17. Moreover, the CD4-8- T cell-derived MIF was found to be the major enhancer and TGF-beta the principal inhibitor of CD4+ and CD8+ T cell cytokine production in these studies. We believe that decreases in the CD48 subset may diminish protective immunity in aging, whereas increases in this subset may augment the severity of autoimmune diseases. As several immune subsets have been shown to be dramatically change in numbers and percentages with age and during various disease states, we believe that more detailed analysis of these subsets, their cytokine expression profile and their role in disease progression will not only yield valuable information about the immune deficits associated with aging and disease but may also lead to possible immunotherapeutic interventions to boost immune responses.